This application requests five years of support for the Conte Center for the Neuroscience of Mental Disorders (CCNMD): The Neurobiology of Suicidal Behavior. The Surgeon General notes that 300,000 suicides per year in the United States and ten times that number of suicide attempts, require a response that involves improving our knowledge regarding the relative importance of multiple predictors of suicide risk. The CCNMD employs a multi-disciplinary approach to develop a predictive and explanatory model for suicidal behavior. Project 1: Involves animal studies of genes regulating serotonin function and related behavioral traits of aggression, impulsivity and anxiety that modulate the risk for suicidal acts. Project 2: In the brainstem of depressed suicides we have found fewer serotonin neurons expressing the serotonin transporter gene. We will determine whether this is related to suicide or major depression and assay gene transcription factors as an explanation. CCNMD investigators have identified altered serotonin function in ventral prefrontal cortex and amygdala of suicide victims that may underlie increased impulsivity and suicide risk. We will now study target neurons in the ventral prefrontal cortex to determine their integrity in suicide Project 3: We will use PET to determine whether the postmortem receptor changes associated with major depression and suicide can be distinguished in vivo. Project 4: CCNMD investigators have found evidence for a stress-diathesis model where lifetime impulsivity is a major correlate of past suicide attempts in a sample of over 340 patients with major depression, schizophrenia or borderline personality disorder. Cross-sectional identification of potential risk factors Identifying such predictors will facilitate inception of controlled treatment studies, which are almost non-existent at present. Projects 5 and 6 are studies of familial transmission of suicidality, aggression/impulsivity, serotonin candidate genes, and psychopathology from our adult probands with major depression to their offspring and from parents to our adolescent probands. These studies will evaluate familial influences on the risk for suicide attempts. Project 7 addresses the statistical challenges of large postmortem and in vivo imaging data sets and proposes a set of new and semi-automated strategies.